title: Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate.
abstract: The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.
authors.affiliation: Department of Pathology, Faculty of Medicine, University Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia. veera@um.edu.my.
authors.forename: Veera S
authors.initials: VS
authors.lastname: Nadarajan
authors.affiliation: Department of Pathology, Faculty of Medicine, University Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.|Clinical Haematology Laboratory, Department of Haematology, Hospital Ampang, Kuala Lumpur, Malaysia.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Phan
authors.affiliation: Department of Pathology, Faculty of Medicine, University Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.
authors.forename: Chow-Hiang
authors.initials: CH
authors.lastname: Ang
authors.affiliation: Department of Pathology, Faculty of Medicine, University Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.
authors.forename: Kai-Ling
authors.initials: KL
authors.lastname: Liang
authors.affiliation: Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Gin-Gin
authors.initials: GG
authors.lastname: Gan
authors.affiliation: Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ping-Chong
authors.initials: PC
authors.lastname: Bee
authors.affiliation: Department of Haematology, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Zubaidah
authors.initials: Z
authors.lastname: Zakaria
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D015465:Leukemia, Myeloid, Accelerated Phase / Q000188:drug therapy / Q000235:genetics; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate